الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
Titanium dioxide (TiO2) has been extensively employed in a variety of applications
for decades due to its distinctive physical and chemical characteristics, such as a high
refractive index and absorptive properties. However, as nanotechnologies advance, TiO2-
NPs with their beneficial characteristics are being manufactured and employed more
frequently. As a result, higher environmental and human exposure is predicted, prompting
toxicological studies of TiO2-NPs. Because the liver is usually the first organ to come into
touch with MNPs after ingestion, toxic effects of MNPs on the liver (hepatotoxicity) are a
major concern in nanomedicine today. The generation of reactive oxygen species is one
among nanoparticles’ (NPs) harmful mechanisms.
MicroRNAs (miRNAs) are noncoding short RNA molecules (21–25 nt) that target
mRNA and control protein and gene transcription in a sequence-specific approach at the
post-transcriptional level. They are involved in cell proliferation, differentiation, and death
in many ways. However, given the large number of miRNA genes, their diverse expression
patterns, and the large number of possible miRNA targets, miRNAs are expected to be
implicated in high proportion of human disorders. The changes in their expression have
been linked to diseased states in pathological conditions.
Micro RNA-27 group includes miRNA-27a and miRNA-27b, which are transcribed
from different chromosomes and contain nucleotides variations at the 3’ end. Micro RNA-
27a was discovered on chromosome 19 and was found to have an important function in
tumor formation. Micro RNA-27a has an important function in polymorphisms,
carcinogenesis, growth, apoptosis, migration, as well as angiogenesis, and can influence
drug sensitivity, cancer therapy, and patient prognosis. In cancers such as colon cancer,
pancreatic tumor, breast tumors, bladder cancer, as well as hepatocellular carcinoma,
miRNA-27a can be oncogenic or tumor suppressor. By reducing fatty acid synthase and
stearoyl-CoA desaturase 1 level, miRNA-27a controls hepatic lipid metabolism and
alleviates NAFLD. The miRNA-27 gene is a powerful biomarker for liver disease.
Nuclear factor erythroid 2-related factor -2 is a transcriptional regulator that controls
genes expression engaged in oxidative stress response as well as drug detoxification to regulate
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cellular defense against toxic and oxidative stimuli. When NRF-2 is activated, cells become
resistant to chemical carcinogens and inflammatory stimuli. NRF-2 has a role in a number of
biological processes, including metabolism and inflammation and antioxidant responses.
Specificity protein-1 refers to the KLF transcription factor, which really is a group of
highly retained transcription factors that regulates biological processes including cell
proliferation and is required for early embryonic development. SP-1 is a poor predictor of
survival in patients with pancreatic cancer, as well as gastric cancer. Although SP-1 is required
for early embryonic as well as postnatal growth in rats, their transcription in mature cells is
restricted, and data suggests that SP-1 expression in rodents and humans diminishes with age.
SP controls the expression of numerous pro-oncogenic genes engaged in cell development
(cyclin D1, EGFR, c-Met), survival (Bcl-2, survivin), angiogenesis (VEGF, VEGFR), and
inflammation.
In liver, miRNA-27a suppresses NRF-2 gene expression in many liver diseases and
hepatocellular cancer. It has been reported that miRNA-27a was up-regulated in liver after
oxidative stress. miRNA-27a may target many transcription factors as well as oxidative
regulation and defense gene family members including NRF-2 and SP-1.
The authors wanted to examine if titanium dioxide nanoparticles in the rat’s liver
affected oxidative state and hepatic expression of miRNA-27a, antioxidant genes NRF-2,
and SP-1. Forty male albino rats were utilized in the study (150-250 gm body weight).
Before and after the experiment, all rats had unrestricted food and water, as well as a
light/dark cycle of 12:12 hours as well as identical environmental conditions. Four groups
(ten rats each) were formed. group I as controls of normal rats that were administered
saline orally. For 14 days, normal rats in group II were administered a suspension of
titanium dioxide NPs at 50 mg/kg BW dosage orally. The titanium dioxide NPs suspension
was administered orally to normal rats in group III at 75 mg/kg BW dosage for two weaks.
For 14 days, normal rats in group IV were administered a suspension of titanium dioxide
NPs at 100 mg/kg BW dosage rally.
The rats were cervical dislocated on the 15th day and sacrificed. Blood was drawn from
the dorsal vein and preserved in tubes as soon as possible. A portion of the blood was combined
with anticoagulant to detach plasma for measuring (FRAP), while the rest was left for 20 minutes
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before it was centrifuged at 3000 rpm for 10 minutes to extract serum for measuring ALT,
AST, GGT activities, and bilirubin level.
After sacrificing rats, the livers from all the rats in different groups were removed, rinsed
with cold saline. Each liver tissue sample subdivided into three parts for determination of
malondialdehyde (MDA) content, total RNA isolation for subsequent determination of hepatic
expression of miRNA-27a, NRF-2 and SP-1 genes using RT-PCR as well as for
histopathological investigation.
Results from the present study demonstrated that AST, ALT, GGT activities and TBIL
level elevated significantly in the three studied groups of rats that were given different TiO2-NPs
dosages in comparison to controls. This increase was in a dose dependent manner. Moreover,
this study revealed significant elevation in hepatic malondialdehyde (MDA) content with
simultaneous reduction in ferric reducing antioxidant power in plasma of TiO2-NPs exposed rats
in comparison to controls.
Results from the recent study showed significant up-regulation of hepatic miRNA-27a and
SP-1 gene expressions and NRF-2 reduction in rats treated with different doses of TiO2-NPs
when compared to controls.
from the recent study it could be determined that TiO2-NPs may accumulate in liver tissue
and exert its toxic effect through induction of oxidative stress. Moreover, TiO2-NPs could affect
liver cell integrity predisposing to fibrosis, necrosis and apoptosis. Our study together with
previous ones could refer toxicity to oxidative damage, as a result, nanotoxicity remains an
essential field for more investigation. These observations collectively could shed light not only
on the possible deleterious role of TiO2-NPs exposure upon oxidant status of liver cells but also
on the possibilities of induction of many liver disorders and hepatocellular carcinoma through
modulation of NRF-2 and SP-1 gene expressions and upregulation of their regulatory micro
RNAs namely -27a.